Platelet Bioenergetics and Associations With Delirium and Coma in Patients With Sepsis: A Prospective Cohort Study.

BACKGROUND: Acute brain dysfunction during sepsis, which manifests as delirium or coma, is common and is associated with multiple adverse outcomes, including longer periods of mechanical ventilation, prolonged hospital stays, and increased mortality. Delirium and coma during sepsis may be manifestations of alteration in systemic metabolism. Because access to brain mitochondria is a limiting factor, measurement of peripheral platelet bioenergetics offers a potential opportunity to understand metabolic changes associated with acute brain dysfunction during sepsis. RESEARCH QUESTION: Are altered platelet mitochondrial bioenergetics associated with acute brain dysfunction during sepsis? STUDY DESIGN AND METHODS: We assessed participants with critical illness in the ICU for the presence of delirium or coma via validated assessment measures. Blood samples were collected and processed to isolate and measure platelet mitochondrial oxygen consumption. We used Seahorse extracellular flux to measure directly baseline, proton leak, maximal oxygen consumption rate, and extracellular acidification rate. We calculated adenosine triphosphate-linked, spare respiratory capacity, and nonmitochondrial oxygen consumption rate from the measured values. RESULTS: Maximum oxygen consumption was highest in patients with coma, as was spare respiratory capacity and extracellular acidification rate in unadjusted analysis. After adjusting for age, sedation, modified Sequential Organ Failure Assessment score without the neurologic component, and preexisting cognitive function, increased spare respiratory capacity remained associated with coma. Delirium was not associated with any platelet mitochondrial bioenergetics. INTERPRETATION: In this single-center exploratory prospective cohort study, we found that increased platelet mitochondrial spare respiratory capacity was associated with coma in patients with sepsis. Future studies powered to determine any relationship between delirium and mitochondrial respiration bioenergetics are needed.

Effect of Atypical Sleep EEG Patterns on Weaning From Prolonged Mechanical Ventilation.

BACKGROUND: Approximately one-third of acute ICU patients display atypical sleep patterns that cannot be interpreted by using standard EEG criteria for sleep. Atypical sleep patterns have been associated with poor weaning outcomes in acute ICUs. RESEARCH QUESTION: Do patients being weaned from prolonged mechanical ventilation experience atypical sleep EEG patterns, and are these patterns linked with weaning outcomes? STUDY DESIGN AND METHODS: EEG power spectral analysis during wakefulness and overnight polysomnogram were performed on alert, nondelirious patients at a long-term acute care facility. RESULTS: Forty-four patients had been ventilated for a median duration of 38 days at the time of the polysomnogram study. Eleven patients (25%) exhibited atypical sleep EEG. During wakefulness, relative EEG power spectral analysis revealed higher relative delta power in patients with atypical sleep than in patients with usual sleep (53% vs 41%; P < .001) and a higher slow-to-fast power ratio during wakefulness: 4.39 vs 2.17 (P < .001). Patients with atypical sleep displayed more subsyndromal delirium (36% vs 6%; P = .027) and less rapid eye movement sleep (4% vs 11% total sleep time; P < .02). Weaning failure was more common in the atypical sleep group than in the usual sleep group: 91% vs 45% (P = .013). INTERPRETATION: This study provides the first evidence that patients in a long-term acute care facility being weaned from prolonged ventilation exhibit atypical sleep EEG patterns that are associated with weaning failure. Patients with atypical sleep EEG patterns had higher rates of subsyndromal delirium and slowing of the wakeful EEG, suggesting that these two findings represent a biological signal for brain dysfunction.

Estimated Cerebral Perfusion Pressure and Intracranial Pressure in Septic Patients.

BACKGROUND: Sepsis-associated brain dysfunction (SABD) is frequent and is associated with poor outcome. Changes in brain hemodynamics remain poorly described in this setting. The aim of this study was to investigate the alterations of cerebral perfusion pressure and intracranial pressure in a cohort of septic patients. METHODS: We conducted a retrospective analysis of prospectively collected data in septic adults admitted to our intensive care unit (ICU). We included patients in whom transcranial Doppler recording performed within 48 h from diagnosis of sepsis was available. Exclusion criteria were intracranial disease, known vascular stenosis, cardiac arrhythmias, pacemaker, mechanical cardiac support, severe hypotension, and severe hypocapnia or hypercapnia. SABD was clinically diagnosed by the attending physician, anytime during the ICU stay. Estimated cerebral perfusion pressure (eCPP) and estimated intracranial pressure (eICP) were calculated from the blood flow velocity of the middle cerebral artery and invasive arterial pressure using a previously validated formula. Normal eCPP was defined as eCPP ≥ 60 mm Hg, low eCPP was defined as eCPP < 60 mm Hg; normal eICP was defined as eICP ≤ 20 mm Hg, and high eICP was defined as eICP > 20 mm Hg. RESULTS: A total of 132 patients were included in the final analysis (71% male, median [interquartile range (IQR)] age was 64 [52-71] years, median [IQR] Acute Physiology and Chronic Health Evaluation II score on admission was 21 [15-28]). Sixty-nine (49%) patients developed SABD during the ICU stay, and 38 (29%) were dead at hospital discharge. Transcranial Doppler recording lasted 9 (IQR 7-12) min. Median (IQR) eCPP was 63 (58-71) mm Hg in the cohort; 44 of 132 (33%) patients had low eCPP. Median (IQR) eICP was 8 (4-13) mm Hg; five (4%) patients had high eICP. SABD occurrence and in-hospital mortality did not differ between patients with normal eCPP and patients with low eCPP or between patients with normal eICP and patients with high eICP. Eighty-six (65%) patients had normal eCPP and normal eICP, 41 (31%) patients had low eCPP and normal eICP, three (2%) patients had low eCPP and high eICP, and two (2%) patients had normal eCPP and high eICP; however, SABD occurrence and in-hospital mortality were not significantly different among these subgroups. CONCLUSIONS: Brain hemodynamics, in particular CPP, were altered in one third of critically ill septic patients at a steady state of monitoring performed early during the course of sepsis. However, these alterations were equally common in patients who developed or did not develop SABD during the ICU stay and in patients with favorable or unfavorable outcome.

Prophylactic Minocycline for Delirium in Critically Ill Patients: A Randomized Controlled Trial.

BACKGROUND: Delirium is a potentially severe form of acute encephalopathy. Minocycline has neuroprotective effects in animal models of neurologic diseases; however, data from human studies remain scarce. RESEARCH QUESTION: Does the neuroprotective effect of minocycline prevent delirium occurrence in critical ill patients? STUDY DESIGN AND METHODS: This study was a randomized, placebo-controlled, double-blind trial conducted in four ICUs. Patients aged 18 years or older were eligible and randomized to receive minocycline (100 mg, twice daily) or placebo. The primary outcome was delirium incidence within 28 days or before ICU discharge. Secondary outcomes included days in delirium during ICU stay, delirium/coma-free days, length of mechanical ventilation, ICU length of stay, ICU mortality, and hospital mortality. The kinetics of various inflammatory (IL-1ß, IL-6, IL-10, and C-reactive protein) and brain-related biomarkers (brain-derived neurotrophic factor and S100B) were used as exploratory outcomes. RESULTS: A total of 160 patients were randomized, but one patient in the placebo group died before treatment; thus the data from 159 patients were analyzed (minocycline, n = 84; placebo, n = 75). After the COVID-19 pandemic it was decided to stop patient inclusion early. There was a small but significant decrease in delirium incidence: 17 patients (20%) in the minocycline arm compared with 26 patients (35%) in the placebo arm (P = .043). No other delirium-related outcomes were modified by minocycline treatment. Unexpectedly, there was a significant decrease in hospital mortality (39% vs. 23%; P = .029). Among all analyzed biomarkers, only plasma levels of C-reactive protein decreased significantly after minocycline treatment (F = 0.75, P = .78, within time; F = 4.09, P = .045, group × time). INTERPRETATION: Our findings in this rather small study signal a possible positive effect of minocycline on delirium incidence. Further studies are needed to confirm the benefits of this drug as a preventive measure in critically ill patients. CLINICAL TRIAL REGISTRATION: ClinicalTrials.gov; No.: NCT04219735; URL: www. CLINICALTRIALS: gov.

Assessment of autonomic symptom scales in patients with neurodevelopmental diagnoses using electronic health record data.

Background: Sleep disturbances, gastrointestinal problems, and atypical heart rate are commonly observed in patients with autism spectrum disorder (ASD) and may relate to underlying function of the autonomic nervous system (ANS). The overall objective of the current study was to quantitatively characterize features of ANS function using symptom scales and available electronic health record (EHR) data in a clinically and genetically characterized pediatric cohort. Methods: We assessed features of ANS function via chart review of patient records adapted from items drawn from a clinical research questionnaire of autonomic symptoms. This procedure coded for the presence and/or absence of targeted symptoms and was completed in 3 groups of patients, including patients with a clinical neurodevelopmental diagnosis and identified genetic etiology (NPD, n=244), those with an ASD diagnosis with no known genetic cause (ASD, n=159), and age and sex matched controls (MC, n=213). Symptoms were assessed across four main categories: (1) Mood, Behavior, and Emotion; (2) Secretomotor, Sensory Integration; (3) Urinary, Gastrointestinal, and Digestion; and (4) Circulation, Thermoregulation, Circadian function, and Sleep/Wake cycles. Results: Chart review scores indicate an increased rate of autonomic symptoms across all four sections in our NPD group as compared to scores with ASD and/or MC. Additionally, we note several significant relationships between individual differences in autonomic symptoms and quantitative ASD traits. Conclusion: These results highlight EHR review as a potentially useful method for quantifying variance in symptoms adapted from a questionnaire or survey. Further, using this method indicates that autonomic features are more prevalent in children with genetic disorders conferring risk for ASD and other neurodevelopmental diagnoses.

GLUT-1 changes in paediatric Huntington disease brain cortex and fibroblasts: an observational case-control study.

BACKGROUND: Paediatric Huntington disease with highly expanded mutations (HE-PHD; >80 CAG repeats) presents atypically, compared to adult-onset Huntington disease (AOHD), with neurodevelopmental delay, epilepsy, abnormal brain glucose metabolism, early striatal damage, and reduced lifespan. Since genetic GLUT-1 deficiency syndrome shows a symptom spectrum similar to HE-PHD, we investigated the potential role of the two main glucose transporters, GLUT-1 and GLUT-3, in HE-PHD. METHODS: We compared GLUT-1 and GLUT-3 protein expression in HE-PHD, juvenile-onset (JOHD), and AOHD brains (n = 2; n = 3; n = 6) and periphery (n = 3; n = 2; n = 2) versus healthy adult controls (n = 6; n = 6). We also investigated mitochondrial complexes and hexokinase-II protein expression. FINDINGS: GLUT-1 and GLUT-3 expression were significantly lower in HE-PHD frontal cortex (p = 0.009, 95% [CI 13.4, 14.7]; p = 0.017, 95% [CI 14.2, 14.5]) versus controls. In fibroblasts, GLUT-1 and GLUT-3 expression were lower compared to controls (p < 0.0001, 95% [CI 0.91, 1.09]; p = 0.046, 95% [CI 0.93, 1.07]). In the frontal cortex, this occurred without evidence of extensive neuronal degeneration. Patients with HE-PHD had deregulated mitochondrial complex expression, particularly complexes II-III, levels of which were lower in frontal cortex versus controls (p = 0.027, 95% [CI 17.1, 17.6]; p = 0.002, 95% CI [16.6, 16.9]) and patients with AOHD (p = 0.052, 95% [CI 17.0, 17.6]; p = 0.002, 95% [CI 16.6, 16.7]). Hexokinase-II expression was also lower in HE-PHD frontal cortex and striatum versus controls (p = 0.010, 95% [CI 17.8, 18.2]; p = 0.045, 95% [CI 18.6, 18.7]) and in frontal cortex versus patients with AOHD (p = 0.013, 95% [CI 17.7, 18.1]). Expression JOHD levels were consistently different to those of HE-PHD but similar to those of AOHD. INTERPRETATION: Our data suggest a dysfunctional hypometabolic state occurring specifically in paediatric Huntington disease brains. FUNDING: '5 × 1000' Personal Income Tax donation to LIRH Foundation; Italian Ministry of HealthRC2301MH04 and RF-2016-02364123 to CSS.

Growth variables and obstetrical risk factors in newborns are associated with psychomotor development at preschool age.

BACKGROUND: Low birthweight resulting from preterm birth or fetal growth restriction is associated with poor neurocognitive development and child psychopathology affecting school performance and educational success. Prediction of developmental performance may therefore serve as a basis for early intervention strategies to improve educational success and mental health of our children in a timely manner. OBJECTIVE: This study aimed to explore the predictive capacity of morphometric variables taken at birth and that of obstetrical risk factors to predict developmental performance at 4.3 (standard deviation, 0.8) years preschool age. We examined predicted Total psychomotor development score, predicted Developmental disability index, calculated Morphometric vitality index, and predicted Intelligence quotient, Maze test, and Neurologic examination optimality score in a large prospective screening (cranial ultrasound screening, n=5,301) and validation cohort (n=508,926). STUDY DESIGN: In a single-center cohort observational study design (data collection done from 1984-1988, analysis done in 2022), a prospective cranial ultrasound screening study (1984-1988) was carried out on 5,301 live-born infants, including 571 (10.8%) preterm infants (≤36 weeks gestation), on the day of discharge of the mother at 5 to 8 days postpartum from a level 3 perinatal center. Predicted psychomotor development as assessed by predicted Total psychomotor development score, predicted Developmental disability index, calculated Morphometric vitality index, and predicted Intelligence quotient, Maze test, and Neurologic examination optimality score, was calculated. We related growth variables and obstetrical risk factors to Psychomotor development indices, and calculated Morphometric vitality index using odds ratios, receiver operating characteristics, analysis of variance, and multivariate analysis of variance. RESULTS: The key result of our study is the observation that simple morphometric measures from newborns at birth like weight/head circumference ratio predict overall psychomotor development at 4.3 years (standard deviation, 0.8) of preschool age. Psychomotor development was assessed by predicted Total psychomotor development score, predicted Intelligence quotient, Maze test, and Neurologic examination optimality score, and related to weight/head circumference ratio in linear regression (P<.001) and ROC curve analyses (P<.001). Further, white matter damage strongly predicted adverse outcome in predicted Developmental disability index (P<.001). There was also a close correlation between calculated Morphometric vitality index and predicted Developmental disability index (P<.001). Finally, brain body weight ratio, weight/head circumference ratio, preterm birth, reduced Apgar at 10 minutes, weight/length ratio, and white matter damage yielded highest odds ratios for adverse outcome in predicted Total psychomotor development score and in predicted Developmental disability index (P<.001) and high effect sizes in reduced predicted Intelligence quotient, Maze test, and Neurologic examination optimality scores. CONCLUSION: Simple morphometric data, birth variables, and obstetrical risk factors bear predictive capacity for neurocognitive performance in children at 4.3 years (standard deviation, 0.8) of age and hence provide a basis for parental consultation and early intervention to improve school performance, educational success, and mental health in developed and developing countries.

The Pathogenesis of Disinhibition in Patients with Traumatic Brain Injury: A Two Patient Case Report.

Higher brain dysfunction commonly occurs following traumatic brain injury (TBI), and may manifest in a social behavioral impairment which can significantly impede active social participation. We report two cases, one of voyeurism and the second of alcohol abuse, which might have been caused by TBI resulting in disinhibition, a type of social behavioral impairment. We discuss the underlying pathophysiological mechanisms to raise awareness of such cases and aid the development of effective interventions. Patient 1 suffered a TBI at 18 years of age, 2 years after which he presented repeated episodes of sexually deviant behavior (voyeurism). At 28, he committed suicide, since he was unable to control his aberrant behavior. Patient 2 suffered a TBI at the age of 13. He first displayed problematic behavior 7 years later, which included drinking excessive amounts of alcohol and stealing while inebriated. Despite both patients having sound moral judgment, they had irrational and uncontrollable impulses of desire. Imaging findings could explain the possible causes of impulse control impairments. Damage to the basal ganglia and limbic system, which are involved in social behavior, presumably led to desire-dominated behavior, leading to the patients conducting unlawful acts despite intact moral judgment. It is crucial to educate society about the prevalence of these disorders, explain how these disinhibitions start, and develop effective interventions.

Case report: Mitochondrial trifunctional protein deficiency caused by HADHB gene mutation (c.1175C>T) characterized by higher brain dysfunction followed by neuropathy, presented gadolinium enhancement on brain imaging in an adult patient.

Mitochondrial trifunctional protein (MTP) deficiency is an autosomal recessive disorder caused by impaired metabolism of long-chain fatty acids (LCFAs). Childhood and late-onset MTP deficiency is characterized by myopathy/rhabdomyolysis and peripheral neuropathy; however, the features are unclear. A 44-year-old woman was clinically diagnosed with Charcot-Marie-Tooth disease at 3 years of age due to gait disturbance. Her activity and voluntary speech gradually decreased in her 40s. Cognitive function was evaluated and brain imaging tests were performed. The Mini-Mental State Examination and frontal assessment battery scores were 25/30 and 10/18, respectively, suggesting higher brain dysfunction. Peripheral nerve conduction studies revealed axonal impairments. Brain computed tomography showed significant calcification. Magnetic resonance imaging revealed an increased gadolinium contrast-enhanced signal in the white matter, suggesting demyelination of the central nervous system (CNS) due to LCFAs. The diagnosis of MTP deficiency was confirmed through genetic examination. Administration of L-carnitine and a medium-chain fatty triglyceride diet was initiated, and the progression of higher brain dysfunction was retarded within 1 year. This patient's presentation was suggestive of CNS demyelination. The presence of brain calcification, higher brain dysfunction, or gadolinium enhancement in the white matter in patients with peripheral neuropathy may be suggestive of MTP deficiency.

The association between the presence and burden of periodic discharges and outcome in septic patients: an observational prospective study.

BACKGROUND: Sepsis-associated encephalopathy (SAE) is frequent in septic patients. Electroencephalography (EEG) is very sensitive to detect early epileptic abnormalities, such as seizures and periodic discharges (PDs), and to quantify their duration (the so-called burden). However, the prevalence of these EEG abnormalities in septic patients, as well as their effect on morbidity and mortality, are still unclear. The aims of this study were to assess whether the presence of electrographic abnormalities (i.e. the absence of reactivity, the presence and burden of seizures and PDs) was associated with functional outcome and mortality in septic patients and whether these abnormalities were associated with sepsis-associated encephalopathy (SAE). METHODS: We prospectively included septic patients, without known chronic or acute intracranial disease or pre-existing acute encephalopathy, requiring ICU admission in a tertiary academic centre. Continuous EEG monitoring was started within 72 h after inclusion and performed for up to 7 days. A comprehensive assessment of consciousness and delirium was performed twice daily by a trained neuropsychologist. Primary endpoints were unfavourable functional outcome (UO, defined as a Glasgow Outcome Scale-Extended-GOSE-score < 5), and mortality collected at hospital discharge and secondary endpoint was the association of PDs with SAE. Mann-Whitney, Fisher's exact and χ2 tests were used to assess differences in variables between groups, as appropriate. Multivariable logistic regression analysis with in-hospital mortality, functional outcome, SAE or PDs as the dependent variables were performed. RESULTS: We included 92 patients. No seizures were identified. Nearly 25% of patients had PDs. The presence of PDs and PDs burden was associated with UO in univariate (n = 15 [41%], p = 0.005 and p = 0.008, respectively) and, for PDs presence, also in multivariate analysis after correcting for disease severity (OR 3.82, IC 95% [1.27-11.49], p = 0.02). The PDs burden negatively correlated with GOSE (Spearman's coefficient ρ = - 0.2, p = 0.047). The presence of PDs was also independently associated with SAE (OR 8.98 [1.11-72.8], p = 0.04). Reactivity was observed in the majority of patients and was associated with outcomes (p = 0.044 for both functional outcome and mortality). CONCLUSION: Our findings suggest that PDs and PDs burden are associated with SAE and might affect outcome in septic patients.

Neurofilament light chains to assess sepsis-associated encephalopathy: Are we on the track toward clinical implementation?

Sepsis is the most common cause of admission to intensive care units worldwide. Sepsis patients frequently suffer from sepsis-associated encephalopathy (SAE) reflecting acute brain dysfunction. SAE may result in increased mortality, extended length of hospital stay, and long-term cognitive dysfunction. The diagnosis of SAE is based on clinical assessments, but a valid biomarker to identify and confirm SAE and to assess SAE severity is missing. Several blood-based biomarkers indicating neuronal injury have been evaluated in sepsis and their potential role as early diagnosis and prognostic markers has been studied. Among those, the neuroaxonal injury marker neurofilament light chain (NfL) was identified to potentially serve as a prognostic biomarker for SAE and to predict long-term cognitive impairment. In this review, we summarize the current knowledge of biomarkers, especially NfL, in SAE and discuss a possible future clinical application considering existing limitations.

Altered Tryptophan-Kynurenine Pathway in Delirium: A Review of the Current Literature.

Delirium, a common form of acute brain dysfunction, is associated with increased morbidity and mortality, especially in older patients. The underlying pathophysiology of delirium is not clearly understood, but acute systemic inflammation is known to drive delirium in cases of acute illnesses, such as sepsis, trauma, and surgery. Based on psychomotor presentations, delirium has three main subtypes, such as hypoactive, hyperactive, and mixed subtype. There are similarities in the initial presentation of delirium with depression and dementia, especially in the hypoactive subtype. Hence, patients with hypoactive delirium are frequently misdiagnosed. The altered kynurenine pathway (KP) is a promising molecular pathway implicated in the pathogenesis of delirium. The KP is highly regulated in the immune system and influences neurological functions. The activation of indoleamine 2,3-dioxygenase, and specific KP neuroactive metabolites, such as quinolinic acid and kynurenic acid, could play a role in the event of delirium. Here, we collectively describe the roles of the KP and speculate on its relevance in delirium.

Pu-erh tea alleviated colitis-mediated brain dysfunction by promoting butyric acid production.

Brain inflammation develops with increased colitis. Pu-erh tea is considered a potential dietary intervention to improve colitis. However, it's unclear whether Pu-erh tea helps alleviate colitis-mediated brain dysfunction. Here, we found that colitis triggered brain dysfunction and increased the risk of depression. Pu-erh tea improved gut-brain barrier function (increased ZO-1 and Occludin) and restored short-chain fatty acids (SCFAs) as well as neurotransmitter release (γ-GABA, 5-HT, and dopamine), which stemmed from the production of butyric acid (BA). Pu-erh tea and BA promoted the production of SCFAs by reshaping the gut microbes (increased Lactobacillus, Akkermansia, Faecalibaculum), thereby downregulating gut inflammatory protein expression (PI3K/AKT/NF-κB). SCFAs, especially BA, intervened directly in the blood-brain barrier via the gut-brain axis to restore neurotransmitter release. Collectively, our results highlighted that increasing BA through Pu-erh tea consumption may be a key mechanism for improving colitis-mediated brain dysfunction by lowering gut inflammation and balancing gut microbe-gut-brain axis homeostasis. These results provide a promising step that might encourage further investigations of Pu-erh tea as a protective agent for brain function in colitis patients.

Altered Functional Networks of Alpha and Low-Beta Bands During Upper Limb Movement and Association with Motor Impairment in Chronic Stroke.

Background: Impaired movement after stroke is closely associated with altered brain functions, and thus the investigation on neural substrates of patients with stroke can pave a way for not only understanding the underlying mechanisms of neuropathological traits, but also providing an innovative solution for stroke rehabilitation. The objective of this study was to precisely investigate altered brain functions in terms of power spectral and brain network analyses. Methods: Altered brain function was investigated by using electroencephalography (EEG) measured while 34 patients with chronic stroke performed movement tasks with the affected and unaffected hands. The relationships between functional brain network indices and Fugl-Meyer Assessment (FMA) scores were also investigated. Results: A stronger low-beta event-related desynchronization was found in the contralesional hemisphere for both affected and unaffected movement tasks compared with that of the ipsilesional hemisphere. More efficient whole-brain networks (increased strength and clustering coefficient, and prolonged path length) in the low-beta frequency band were revealed when moving the unaffected hand compared with when moving the affected hand. In addition, the brain network indices of the contralesional hemisphere indicated higher efficiency and cost-effectiveness than those of the ipsilesional hemisphere in both the alpha and low-beta frequency bands. Moreover, the alpha network indices (strength, clustering coefficient, path length, and small-worldness) were significantly correlated with the FMA scores. Conclusions: Efficient functional brain network indices are associated with better motor outcomes in patients with stroke and could be useful biomarkers to monitor stroke recovery during rehabilitation.

Role of Brain-Gut-Microbiota Axis in Depression: Emerging Therapeutic Avenues.

The human gut microbiota plays a significant role in the pathophysiology of central nervous system-related diseases. Recent studies suggest correlations between the altered gut microbiota and major depressive disorder (MDD). It is proposed that normalization of the gut microbiota alleviates MDD. The imbalance of brain-gut-microbiota axis also results in dysregulation of the hypothalamicpituitary- adrenal (HPA) axis. This imbalance has a crucial role in the pathogenesis of depression. Treatment strategies with certain antibiotics lead to the depletion of useful microbes and thereby induce depression like effects in subjects. Microbiota is also involved in the synthesis of various neurotransmitters (NTs) like 5-hydroxy tryptamine (5-HT; serotonin), norepinephrine (NE) and dopamine (DA). In addition to NTs, the gut microbiota also has an influence on brain derived neurotrophic factor (BDNF) levels. Recent research findings have exhibited that transfer of stress prone microbiota in mice is also responsible for depression and anxiety-like behaviour in animals. The use of probiotics, prebiotics, synbiotics and proper diet have shown beneficial effects in the regulation of depression pathogenesis. Moreover, transplantation of fecal microbiota from depressed individuals to normal subjects also induces depression-like symptoms. With the precedence of limited therapeutic benefits from monoamine targeting drugs, the regulation of brain-gut microbiota is emerging as a new treatment modality for MDDs. In this review, we elaborate on the significance of brain-gut-microbiota axis in the progression of MDD, particularly focusing on the modulation of the gut microbiota as a mode of treating MDD.

Post-Transjugular Intrahepatic Portosystemic Shunt (TIPS) Hepatic Encephalopathy-A Review of the Past Decade's Literature Focusing on Incidence, Risk Factors, and Prophylaxis.

Transjugular intrahepatic portosystemic shunt (TIPS) is an established treatment for portal hypertension and its' complications in liver cirrhosis, yet the development of hepatic encephalopathy (HE) remains a significant concern. This review covers the reported incidence, risk factors, and management strategies for post-TIPS HE over the past decade. Incidence varies widely (7-61%), with factors like age, liver function, hyponatremia, and spontaneous portosystemic shunts influencing risk. Procedural aspects, including TIPS timing, indication, and stent characteristics, also contribute. Pharmacological prophylaxis with lactulose and rifaximin shows promise, but current evidence is inconclusive. Procedural preventive measures, such as shunt embolization and monitoring portal pressure gradients, are explored. Treatment involves pharmacological options like lactulose and rifaximin, and procedural interventions like stent diameter reduction. Ongoing studies on novel predictive markers and emerging treatments, such as faecal microbiota transplant, reflect the evolving landscape in post-TIPS HE management. This concise review provides clinicians with insights into the multifaceted nature of post-TIPS HE, aiding in improved risk assessment, prophylaxis, and management for patients undergoing TIPS procedures.

Case report: Fatal Borna virus encephalitis manifesting with basal brain and brainstem symptoms.

Background: Since the first report of fatal Borna virus-1 (BoDV-1) encephalitis in 2018, cases gradually increased. There is a lack of diagnostic algorithm, and there is no effective treatment so far. Case presentation: We report an acute BoDV-1 encephalitis in a 77-year-old female with flu-like onset, rapid progression to word-finding difficulties, personality changes, global disorientation, diffuse cognitive slowness, and gait ataxia and further deterioration with fever, meningism, severe hyponatremia, epileptic seizures, cognitive decline, and focal cortical and cerebellar symptoms/signs. The extensive diagnostic workup (cerebrovascular fluid, serum, and MRI) for (meningo-)encephalitis was negative for known causes. Our empirical common antiviral, antimicrobial, and immunosuppressive treatment efforts failed. The patient fell into coma 5 days after admission, lost all brainstem reflexes on day 18, remained fully dependent on invasive mechanical ventilation thereafter and died on day 42. Brain and spinal cord autopsy confirmed an extensive, diffuse, and severe non-purulent, lymphocytic sclerosing panencephalomyelitis due to BoDV-1, affecting neocortical, subcortical, cerebellar, neurohypophysis, and spinal cord areas. Along with our case, we critically reviewed all reported BoDV-1 encephalitis cases. Conclusion: The diagnosis of acute BoDV-1 encephalitis is challenging and delayed, while it progresses to fatal. In this study, we list all tried and failed treatments so far for future reference and propose a diagnostic algorithm for prompt suspicion and diagnosis.

Gamma oscillations and application of 40-Hz audiovisual stimulation to improve brain function.

BACKGROUND: Audiovisual stimulation, such as auditory stimulation, light stimulation, and audiovisual combined stimulation, as a non-invasive stimulation, which can induce gamma oscillation, has received increased attention in recent years, and it has been preliminarily applied in the clinical rehabilitation of brain dysfunctions, such as cognitive, language, motor, mood, and sleep dysfunctions. However, the exact mechanism underlying the therapeutic effect of 40-Hz audiovisual stimulation remains unclear; the clinical applications of 40-Hz audiovisual stimulation in brain dysfunctions rehabilitation still need further research. OBJECTIVE: In order to provide new insights into brain dysfunction rehabilitation, this review begins with a discussion of the mechanism underlying 40-Hz audiovisual stimulation, followed by a brief evaluation of its clinical application in the rehabilitation of brain dysfunctions. RESULTS: Currently, 40-Hz audiovisual stimulation was demonstrated to affect synaptic plasticity and modify the connection status of related brain networks in animal experiments and clinical trials. Although its promising efficacy has been shown in the treatment of cognitive, mood, and sleep impairment, research studies into its application in language and motor dysfunctions are still ongoing. CONCLUSIONS: Although 40-Hz audiovisual stimulation seems to be effective in treating cognitive, mood, and sleep disorders, its role in language and motor dysfunctions has yet to be determined.

Higher scores on autonomic symptom scales in pediatric patients with neurodevelopmental disorders of known genetic etiology.

INTRODUCTION: Features of underlying autonomic dysfunction, including sleep disturbances, gastrointestinal problems, and atypical heart rate, have been reported in neurodevelopmental conditions, including autism spectrum disorder (ASD). The current cross-sectional, between-groups study aimed to quantify symptoms of autonomic dysfunction in a neurodevelopmental pediatric cohort characterized by clinical diagnoses as well as genetic etiology. METHOD: The Pediatric Autonomic Symptom Scales (PASS) questionnaire was used to assess autonomic features across a group of patients with clinical neurodevelopmental diagnoses (NPD; N = 90) and genetic etiologies. Patients were subdivided based on either having a clinical ASD diagnosis (NPD-ASD; n = 37) or other non-ASD neurodevelopmental diagnoses, such as intellectual disability without ASD, speech and language disorders, and/or attention deficit hyperactivity disorder (NPD-OTHER; n = 53). Analyses focused on characterizing differences between the NPD group compared to previously published reference samples, as well as differences between the two NPD subgroups (NPD-ASD and NPD-OTHER). RESULTS: Our results indicate higher PASS scores in our NPD cohort relative to children with and without ASD from a previously published cohort. However, we did not identify significant group differences between our NPD-ASD and NPD-OTHER subgroups. Furthermore, we find a significant relationship between quantitative ASD traits and symptoms of autonomic function. CONCLUSION: This work demonstrates the utility of capturing quantitative estimates of autonomic trait dimensions that may be significantly linked with psychosocial impairments and other core clinical features of ASD.